A Phase II Study on Continuous Infusional Paclitaxel and 5-Fu as First-line Chemotherapy for Patients with Advanced Esophageal Cancer

Esophageal squamous cell carcinoma (ESCC) in China is the fourth most common cancer. ESCC is usually diagnosed at advanced stage, and chemotherapy is a main treatment for ESCC. First-line chemotherapy includes cisplatin (DDP), 5 fluorouracil (5-Fu), paclitaxel (PTX) with response rates (RR) ranging from 40%-60%. One, 3and 5-year survival rates after diagnosis were about 50%, 20% and 10%, respectively, with a median survival time (OS) about 12 months. Effective and well-tolerated chemotherapy is considered to be a modality to prolong OS and to improve quality of life. Thus, reasonable chemotherapeutic modification includes dose and exposure time adjustment of the conventional regimen administered. PTX combined with DDP and 5-Fu is commonly used in the chemotherapy for ESCC, because the combination has the synergy effect (Ekman et al., 2008; Al-Batran et al., 2010; Herskovic et al., 2012; Mirinezhad et al., 2012). It is reported that PTX and 5-Fu with continuously intravenous infusion at low dose could expose cancerous tissue to


Introduction
Esophageal squamous cell carcinoma (ESCC) in China is the fourth most common cancer.ESCC is usually diagnosed at advanced stage, and chemotherapy is a main treatment for ESCC.First-line chemotherapy includes cisplatin (DDP), 5 fluorouracil (5-Fu), paclitaxel (PTX) with response rates (RR) ranging from 40%-60%.One-, 3-and 5-year survival rates after diagnosis were about 50%, 20% and 10%, respectively, with a median survival time (OS) about 12 months.Effective and well-tolerated chemotherapy is considered to be a modality to prolong OS and to improve quality of life.Thus, reasonable chemotherapeutic modification includes dose and exposure time adjustment of the conventional regimen administered.
PTX combined with DDP and 5-Fu is commonly used in the chemotherapy for ESCC, because the combination has the synergy effect (Ekman et al., 2008;Al-Batran et al., 2010;Herskovic et al., 2012;Mirinezhad et al., 2012).It is reported that PTX and 5-Fu with continuously intravenous infusion at low dose could expose cancerous tissue to

A Phase II Study on Continuous Infusional Paclitaxel and 5-Fu as First-line Chemotherapy for Patients with Advanced Esophageal Cancer
Ming Gu 1 , Su-Yi Li 2 *, Xin-En Huang 3 *, Yan Lin 4 , Hong-Yan Cheng 2 , Lin Liu 2 cytotoxic agents at relatively constant concentration, and reduce adverse reactions compared with short-term infusion (Hainsworth et al., 1997;Pasial et al., 1998;Polee et al., 2002;Bucci et al., 2004;West et al., 2005).We conducted a multi-center clinical trial in order to access the efficacy and toxicity of 16-hours continuous infusional PTX and 24-hours 5-Fu at a low dose as firstline chemotherapy in patients with advanced esophageal squamous cancer.

Eligibility criteria
Oncology department of three comprehensive hospitals in Jiangsu province participated in this study, and the eligible patients of each center not less than 5 cases.All patients involved in the current study were required to be histologically confirmed with ESCC, aged 18-75 years, to have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 and a life expectancy of ≥3 months.Patients were staged III or IV ESCC and not indicated for surgery.The patients Treatment protocol PTX 20 mg/m 2 was administered through a 16-hours continuously intravenous infusion on days 1 to 3,8 and 9;DDP 3.75 mg/m 2 was given on days 1 to 4 and 8 to 11; continuously infusional 5-Fu was given in 24-hours on days 1 to 5 and 8 to 12 at a dose of 375 mg/m 2 ; folacin 60mg was administrated orally synchronization with 5-Fu, the treatment was repeated every 21 days and at least two cycles.As prophylactic agents, dexamethasone 10 mg was taked 6h before PTX, methyllprednisolone (iv,40 mg ), promethazine (iv, 12.5 mg) and cimetidine (iv, 400 mg) were given 30 min before paclitaxel.
All patients received full blood count, hepatic and renal functions and ECG to evaluate the safety and adverse effect before and after each cycle of chemotherapy.After two cycles of treatment, a CT scan and examination of barium meal in digestive tract, when necessary, gastroscopy is performed, to evaluate the response to treatment and the tolerability to chemotherapy.

Treatment assessment
All patients should be followed up till disease progression, which was conformed by imaging technology, and document time to progression.Evaluation of response was carried out according to RECIST criteria, including complete response (CR), partial response (PR), stable (SD) and progress (PD), overall response rate (RR)= CR + PR.Adverse reaction was evaluated according to National Cancer Institute Common Toxicity Criteria version 3.0 (NCI-CTC).

Patient Characteristics
22 cases were evaluable, with 16 males and 6 females, the median age was 63 years, ranged between 42 and 71 years.ECOG Performance status (PS) was 0-1 in 13 patients and was 2 in 9 patients.22 patients were proved in stage IV or recurrence patients.Amount to 18 patients lost weight ≥5% nearly two month.2 cases were high differentiated, 3 cases were poor differentiated, and the rest were moderate differentiated.Among all eligible patients, 15 had supraclavicular and mediastinal lymph nodes metastasis, 7 had pulmonary, 5 liver, 2 celiac, and 1 pleural metastases.Seven patients had multiple metastases.Nine of 14 patients, who had no surgical history, were medullary type,4 were mushroom type, 1 were ulcer type; 2 tumor focuses were located in cervical segments, 6 in upper thoracic segments, 8 in middle thoracic segments, 1 in  All patients completed at least 2 and above cycles chemotherapy, the median cycles of chemotherapy are 4, follow-up time is respectively 8 ~ 16 months and the median time are for nine months.

Efficacy in short-term and long-term
Twenty two cases were evaluable, 2 CR, 9 PR, 5 SD, and 2 PD were documented with an overall response rate of 68.2% (15/22).The median time to progression was 7.0 months.Patient quality of life (QOL) was improved significantly.

Adverse reactions
Adverse reactions related to chemotherapy were tolerable; the most common toxic effects were bone marrow suppression, alopecia, and fatigue.The incidence of leukiopenia was in research/control group was respectively 59.1%, 27.3% of which occurred with grade 3/4 intensity.The mean time when the leucocyte began to decline was the 14 days in chemotherapy cycle, 27 cycles of which lead to postpone the next cycle , the postponed period neither exceeded one week.The incidence of alopecia was respectively 90.9%.The other kinds of adverse reactions related to treatment were mild, such as diarrhea, constipation, myalgia and arthralgia, peripheral neuritis, dysfunction of liver and hand-foot syndrome, no grade 3-4 nausea and vomiting was observed in this study.No allergic reaction and treatment-related deaths were recorded among all the patients.

Discussion
A standard chemotherapy for ESCC has not yet been established, because of the absence of enough clinical evidence from randomized phase III trail.Combination chemotherapy could obtain response rate of 20%-80% when treating patients in this setting.Currently, the most frequently used chemotherapeutic agent for patients with esophageal cancer was paclitaxel, and commonly combined with DDP and/or 5-Fu, due to the synergic effect of the combination (Polee et al., 2002;Bucci et al., 2004 ;Orditura et al., 2010;Mirinezhad et al., 2012).Low-dose, continuous infusional paclitaxel is reported to maximally inhibit cancer through reducing the emergence of drugresistant tumor cells (Shade et al., 1998(Shade et al., -1999;;Langer et al., 2007;Bhatt et al., 2010).After an initial report with a response rate of 27% among taxane-resistant patients with breast cancer (Seidman et al., 1996), subsequent trials suggested that the treatment efficacy was improved (Holmes et al., 1998;Markman et al., 1998;Socinski et al., 1998;Socinski et al., 1999;Breathnach et al., 2000).Firstline paclitaxel administered as a prolonged infusion (35 mg/m 2 /24 h continuously infused over 96 h ) in advanced bronchioloalveolar carcinoma (BAC) is active (SWOG 9714).The objective response rate was 14% (all partial responses); 40% of patients demonstrated stable disease.The median progression-free and overall survivals were 5 and 12 months, respectively (West et al., 2005).Twenty four hour continuous infusional paclitaxel combination with oxaliplatin in treating 30 Chinese patients with Ⅲ-Ⅳ stage advanced esophageal squamous cell cancer achieved4 CR, 14 PR, and 4 SD, with RR 60. 0% (WANG et al., 2010).Prolonged infusion paclitaxel was reported effective in other studies, eg., ovarian cancer (Markman et al., 1998) and metastatic breast cancer (Seidman et al., 1996;Holmes et al., 1998).
In SWOG 9714 trial, this schedule was associated with considerable toxicity, mostly grade 3/4 hematological toxicity and fatigue/lethargy, each occurring in roughly half of treated patients.In addition, five deaths in SWOG 9714 trial were suspected to be treatment-related (West et al., 2005).In this trial, PTX dose was reduced to 20mg/ m 2 / day, and 16 hours continuous intravenous infusion on days 1 to 3, 8 and 9.The most common adverse reaction were bone marrow suppression, alopecia, fatigue, and the occurrence of grade 3-4 leukopenia was about 30%, which could be recovered after G-CSF administration.Other frequent symptoms were mild gastrointestinal adverse reaction, especially in elderly or patients in poor condition.Compared with other regimen containing PTX, adverse reaction in this study was relatively low (Socinski et al., 1998Polee et al., 2002;West et al., 2005;Mirinezhad et al., 2012).
Some studies suggested that the combination of low dose 5-Fu with cisplatin (low dose FP) might improve therapeutic efficacy and quality of life for patients with advanced and recurrent gastric cancer, advanced colorectal cancer in 1990s (Hainsworth et al., 1997;Pasial et al., 1998).In contrast, ESCC patients presenting with advanced and/or recurrent disease have a median survival measured in months and should be considered accordingly for therapy.Particularly in light of the absence of an optimal standard therapy, clinical trials are an ideal treatment option for these patients.
In conclusion, low-dose continuous infusional PTX in 16-hours and 5-fu in 24-hours is a promising regimen with good tolerability in treating patients with advanced esophageal squamous cell cancer.
Figure 1.Kaplan-Meier Curve of TTP (by patients, n=22) under thoracic segments.All patients completed at least 2 and above cycles chemotherapy, the median cycles of chemotherapy are 4, follow-up time is respectively 8 ~ 16 months and the median time are for nine months.

Table 1 . Patient Characteristics (n = 22)
Phase II Study of Paclitaxel and 5-Fu as First-line Chemotherapy for Patients with Advanced Esophageal Cancer